Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/34—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/08—Materials for coatings
  • A61L29/085—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
  • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
  • A61L29/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/08—Materials for coatings
  • A61L31/10—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L31/16—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
  • A61L2300/222—Steroids, e.g. corticosteroids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/43—Hormones, e.g. dexamethasone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
  • A61L2300/606—Coatings
  • A61L2300/608—Coatings having two or more layers
  • A61L2300/61—Coatings having two or more layers containing two or more active agents in different layers

Definitions

• the present invention relates to a coating composition for a medical device, a method of coating a medical device and a device coated with the composition.
• it relates to the incorporation of more than one bioactive agent into a coating composition and a method for using the composition to coat an implantable medical device.
• Example 6 relates to spraying a stent with a solution of poly (ethylene- covinyl acetate), polybutyl methacrylate and rapamycin dissolved in tetrahydrofuran followed by spraying the thus-coated stent with a solution of poly (ethyl ene-co-vinyl acetate) polybutyl methacrylate and dexamethasone dissolved in tetrahydrofuran.
• US 6,258,121 and US 6,569,195 disclose a polymeric coating for a stent comprising a blend of a faster releasing hydrophilic polymeric material (such as a polylactic acid polyethelene oxide copolymer) and a second slower releasing hydrophobic material (such as a polylactic acid/polycaprolactone copolymer).
• This polymeric blend can be combined with an active agent such as Taxol which is delivered from the stent to inhibit restenosis following angioplasty.
• an active agent such as Taxol which is delivered from the stent to inhibit restenosis following angioplasty.
• polylactic acid is biodegradable.
• WO 03/035135 (Scimed Life Systems Inc.) discloses another coating composition for a drug- release stent which includes a styrene-isobutylene based block copolymer, paclitaxel and organic solvent.
• the drug release profile for this coating is dependant upon the drug- to-polymer ratio.
• the slow release formulation has a three-fold greater coating weight compared with the moderate release formulation.
• the present invention seeks to provide an improved release system for implantable devices.
• Preferred aspects of the present invention seek to provide a system in which drugs or other biologically active materials are released in a controlled and programmable manner, i.e. at a desired rate and/or over a desired period of time and/or after a predetermined period of time after implantation of the device.
• A is a vinyl acetal group
• B is a vinyl alcohol group
• C is a vinyl acetate group
• x is from 0.8 to 0.9
• y is from 0.1 to 0.2
• z is from 0 to 0.025.
• the vehicle additionally comprises a second compound which is a polymer of Formula 2:
• the proportion of the second compound may be over 50% by weight of the coating composition.
• [A] x — [B] y — [C] z is a compound of Formula 1A:
• Rl and R2 are independently H or an alkyl, alkenyl, alkynyl or aryl group and wherein optionally an alkyl, alkenyl, alkynyl or aryl group may be substituted for any pendent hydrogen atom. More preferably, Rl and R2 are independently C1-C6 alkyl.
• the first compound can be bought "off the shelf, it can also be synthesised from vinylacetate (CH 2 CHOCOCH 3 ). This is hydrolysed to form one of the co-polymers (polyvinylalcohol), reacts with an aldehyde (butyl- 1-al in the preferred embodiment) to form the co-polyvinylacetal co-polymer and itself forms the co-vinylacetate co-polymer.
• vinylacetate CH 2 CHOCOCH 3
• aldehyde butyl- 1-al in the preferred embodiment
• the first compound is a polymer which is poly(vinylbutyral-co-vinyl alcohol-co-vinyl acetate) with an average Mw from 50,000 to 80,000 and with 88 wt% vinyl butyral groups:
• a copolymer of Formula 1 provides an effective vehicle for a bioactive to be released from a medical device such as a stent.
• the exemplary copolymer PVB combines hydrophobicity with good adhesion properties.
• the glass transition temperatures (T g ) are very similar for both classes of copolymers.
• the presence of acetate groups in both copolymers means that the copolymers are more likely to be miscible, and therefore there is less likely to a problem of phase separation.
• the two classes of copolymers are soluble in similar solvents and a simple solvent system can be used therefore to dissolve and apply the coating composition, such as tetrahydrofuran, dichloromethane or chloroform.
• the copolymer combination has a wide range of solubility and can therefore be used with a wide range of bioactives.
• the good compatibility of the preferred copolymer combination is in contrast to other combinations that have been tried such as PVB and polyethylene glycol or PVB with a combination of polyethylene glycol and polypropylene glycol, both of which result in compatibility problems.
• a further advantage of the inventive composition is that it allows greater control and selectivity of the drug release than prior art compositions. For example, many prior art compositions release the drug too quickly for it to have the required effect, and therefore drug release is controlled by the use of polymer-only top coatings or variations in the polyme ⁇ drug ratio of the coating. In particular, the latter can lead to a requirement for coating thicknesses which may compromise coating integrity.
• compositions such as that disclosed in the Cordis reference mentioned above (WO 01/87372), attempt to provide a system which releases two different drugs at different rates with each drug targeting a different region of the wound healing response.
• release profiles of the two drugs are in fact fairly similar, which means that the selectivity aimed for is not achieved.
• the present composition is far more effective at providing a system with distinct and selective release profiles.
• a method for coating a medical device comprising the step of:
• the method additionally comprising the step of:
• the first coating preferably has a vehicle comprising said first compound and said second compound in a ratio from 80:20 to 100:0 (most preferably 98:2) and the second coating preferably has a vehicle comprising said first compound and said second compound in a ratio from 70:30 to 94:6 (most preferably 90:10) .
• the bioactive in the second coating may be the same as that in the first, in the preferred embodiment different bioactives are employed in order to result in different effects in vivo as the bioactives are released over time.
• the first coating composition may include an anti-proliferative agent such as rapamycin and the second coating may include an anti-inflammatory agent such as dexamethasone.
• Other bioactives that can be employed include estradiol, taxol, vincristine, prostaglandins, vinblastine, heparin, or a nitric oxide donor.
• the proportion of bioactive to vehicle may be typically from 1 :9 to 1:1 and is preferably from 1:4 to 1:2.
• a medical device such as a stent or graft-stent
• a coating composition by means of a method as defined above.
• the stent is preferably be formed of a metal but the inventive compositions can adhere to many other materials such as PET, PTFE, nylon, polycarbonate, polypropylene and polyurethane.
• a method of using said device comprising implanting the device in an animal or human body.
• adhesion to the surface can be enhanced by means of the method disclosed in WO 03/024500 (in the name of the present applicant), the contents of which are incorporated herein by reference. Where 100% PVB is used, application directly to an unmodified surface may be sufficient (although adhesion may optionally be enhanced by modification techniques). As the amount of PnVPA is increased in the formulation, surface modification may be required to maintain adequate adhesion.
• Figures 5 to 8 are drug elution profiles for stents which have been coated with compositions in accordance with the present invention where the drugs in question are dexamethasone, rapamycin, 17 ⁇ -estradiol and dexamathasone/rapamycin (dual elution) respectively;
• Figure 9 is a schematic representation of pull-off test equipment.
• Figure 10 is a graph showing the average adhesion strength for various test samples.
• Fig. 1 shows part of the wall 11 of a stent 10 of metallic material.
• a stent 10 of metallic material To solve clinical problems, such as restenosis, produced by the implanting of the stent 10, it is treated as follows.
• PVB poly(vinyl butyral-co-vinyl alcohol-co-vinyl acetate)
• PnVPA poly (1- vinylpyrrolidone-co-vinyl acetate)
• PVB is predominantly hydrophobic and comprises the bulk of the formulation, preferably anything from 70% to 100% . Small additions of the hydrophilic PnVPA give the coating its "programmability" in terms of being able to control the release rate of drugs.
• Layer 12 typically has a thickness of 6-7 microns.
• the rapamycin is provided in a suitable solvent which, after the application of layer 12, is removed by allowing the coating to dry. The drying operation also serves to maintain the activity of the rapamycin.
• the stent is then similarly coated until a second layer 14 comprising dexamethasone in a mixture of the same two polymers.
• the polymers PVB and PnVPA have different proportions by weight than in layer 12.
• Layer 14 typically has a thickness of 3-4 microns.
• the dexamethasone is provided in a suitable solvent which, after application of layer 14, is removed by drying.
• the formulations of layers 12 and 14, and in particular the ratios of the polymers PVB and PnVPA, are selected to release their active agents at respective desired rates.
• the ratio of PVB, which is hydrophobic, to PnvPA, which is hydrophilic is selected so that the dexamethasone is substantially released during the first few hours after implantation to reduce inflammation. Release of the dexamethasone, normally at a reducing rate, may continue for a period of up to ten days.
• Typical ratios for PVB to PnVPA in layer 14 are between 70:30 and 94:6, preferably 90: 10.
• the rapamycin in the lower layer 12 is released more slowly.
• Typical percentages by weight of PVB are 80% to 100%, i.e. layer 12 may be solely PVB with no PnVPA content.
• the preferred ratio of PVB to PnVPA is 98:2.
• the rapamycin is typically released over a period of ten days or more.
• the selective release of the active materials can be carefully controlled with reference to rate of release, duration of release and timing of initiation of release.
• rapamycin may be used as the anti-proliferative agent estradiol, taxol, vincristine, vinblastine, or a nitric oxide donor.
• estradiol may be used as the anti-proliferative agent estradiol, taxol, vincristine, vinblastine, or a nitric oxide donor.
• Appropriate mixtures of drugs may be incorporated in each of layer 12 and 14.
• a primer layer (not shown) may be applied to the surface of stent 10 before the application of layer 12.
• stent 10 Preferably the entire surface of stent 10 is coated, but if desired parts of its surface may remain uncoated.
• layer 14 covers all layer 12, but to achieve certain patterns of release, parts of layer 12 may remain uncoated.
• the stents may be made of a plastics material.
• the drug-eluting coatings disclosed can be used with coronary, peripheral or gastrointestinal stents or with other types of devices such as abdominal aortic aneurysm devices, anastomosis devices, heart valve repair devices, implantable biosensors, pacing and electro stimulation leads, vascular grafts or vena cava filters.
• anti-platelet agents e.g prostaglandins and/or anti-coagulants agents e.g. heparin.
• anti-coagulants agents e.g. heparin.
• implantable devices are coated with three or more layers and such arrangements combine as desired the features of the various described embodiments.
• PVB Poly(vinyl pyrrolidone-co-vinyl acetate), average Mw 50,000 (referred to as PnVPA)
• This example describes the preparation and elution of stents comprising various ratios of PVB/PnVPA and dexamethasone
• Stents were cleaned by immersion in IP A for 30 mins with ultrasound and dried at 100°C overnight. All stents then underwent a surface modification procedure as outlined in WO03024500 by the same applicant.
• the stents were weighed, spray coated with the respective formulations and dried overnight at 40°C under vacuum. Upon weighing the average coating weight of the stents was 442 ⁇ g yielding a dexamethasone content of 89 ⁇ g +/- 8 ⁇ g.
• Each stent was placed on a hook and suspended in a vial containing 8ml of an aqueous release medium with a 5 mm magnetic flea. The vials were placed on a multipoint stirrer set at lOOOrpm and incubated at 37°C.
• the stents were transferred to fresh aliquots of release medium and replaced on the stirrer to resume agitation.
• the solution containing dexamethasone was set aside for analysis.
• This example describes the preparation and elution of stents comprising various ratios of PVB/PnVPA and Rapamycin
• Stents were cleaned by immersion in IPA for 30 mins with ultrasound and dried at 100°C overnight.
• the stents were weighed, spray coated with the respective formulations and dried overnight at 40C under vacuum. Upon weighing the average coating weight of the stents was 755 ⁇ g yielding a rapamycin content of 189 ⁇ g +/- 13 ⁇ g.
• Each stent was placed on a hook and suspended in a vial containing 8ml of an aqueous release medium with a 5mm magnetic flea.
• the vials were placed on a multipoint stirrer set at lOOOrpm and incubated at 37°C.
• the stents were transferred to fresh aliquots of release medium and replaced on the stirrer to resume agitation.
• the solution containing rapamycin was set aside for analysis.
• Three coating solutions were prepared in a blend of chloroform and acetone (80:20 by weight) comprising various ratios of PVB/PnVPA (Table 3). 17 ⁇ -Estrradiol was added to each formulation so that in terms of total solids 25% was 17 ⁇ -Estradiol, 75% polymer.
• the stents were weighed, spray coated with the respective formulations and dried overnight at 40°C under vacuum. Upon weighing the average coating weight of the stents was 904 ⁇ g yielding a 17 ⁇ -Estradiol content of 229 ⁇ g +/- 32 ⁇ g.
• Each stent was placed on a hook and suspended in a vial containing 8ml of an aqueous release medium with a 5mm magnetic flea. The vials were placed on a multipoint stirrer set at lOOOrpm and incubated at 37°C.
• the stents were transferred to fresh aliquots of release medium and replaced on the stirrer to resume agitation.
• the solution containing 17 ⁇ -Estradiol was set aside for analysis.
• This example describes the preparation and elution of stents comprising rapamycin and dexamethasone each contained within a specific ratio of PVB/PnVPA
• Stents were cleaned by immersion in IPA for 30 mins with ultrasound and dried at 100°C overnight.
• a coating solution was prepared made up of PEP 100 and rapamycin in chloroform, so that in terms of total solids 25% was rapamycin, 75% polymer.
• a second coating solution was prepared made of PEP 94 and dexamethasone in a mixture of chloroform and acetone (80:20 by volume), so that in terms of total solids 25% was dexamethasone, 75% polymer.
• the stents were weighed, spray coated in equal amounts with the respective formulations such that the bottom layer comprised PEP 100 with rapamycin and the top layer PEP94 with dexamethasone. The stents were then dried overnight at 40°C under vacuum. Upon weighing the average coating weight of the stents was 680 ⁇ g yielding drug loadings of approx 85 ⁇ g +/- 1 l ⁇ g for each individual drug.
• Each stent was placed on a hook and suspended in a vial containing 8ml of an aqueous release medium with a 5mm magnetic flea.
• the vials were placed on a multipoint stirrer set at lOOOrpm and incubated at 37C.
• the stents were transferred to fresh aliquots of release medium and replaced on the stirrer to resume agitation.
• the solution containing dexamethasone/rapamycin was set aside for analysis.
• concentrations of dexamethasone and rapamycin in each sample were determined from standard curves of absorbance at 241nm and 291nm respectively versus concentration of calibration solutions (see Fig. 8).
• This example describes the preparation and elution of stents comprising 17 ⁇ - estradiol and dexamethasone each contained within a specific ratio of PVB/PnVPA
• the stents were weighed, spray coated in a ratio of 3:1 (estradiol: dexamethasone) with the respective formulations such that the bottom layer comprised PEP94 with 17 ⁇ - estradiol and the top layer PEP90 with dexamethasone. The stents were then dried overnight at 40°C under vacuum.
• each stent was placed on a hook and suspended in a vial containing 8ml. of an aqueous release medium with a 5mm magnetic flea.
• the vials were placed on a multipoint stirrer set at lOOOrpm and incubated at 37°C. After a given time interval (ranging from 1 hour to several days), the stents were transferred to fresh aliquots of release medium and replaced on the stirrer to resume agitation.
• the solution containing dexamethasone/ 17 ⁇ -estradiol was set aside for analysis. Analysis of the samples was carried out using HPLC (Agilent 1100 series).
• 0.25mm thick stainless steel plate was cut to the required size (25 x 50mm), cleaned in 2- propanol, and dried thoroughly.
• Functionalised plates (set 3) were coated with a primer layer of PEP100 at 1 % by weight in chloroform using an airbrush to apply an even coating of around 1.5 milligrams to one side of each plate. This coating was dried at 100°C for 20 hours.
• Untreated set 1, and functionalised set 2 plates were coated with a 1 %w/w PEP94 solution in chloroform, applied by airbrush to give an even coating on one side of the plate of around 15 milligrams.
• the plates were dried at 40°C under reduced pressure for 16 hours.
• each plate to be tested was soaked with a solution of 0.01 %w/w aqueous sodium dodecyl sulphate for two hours. The sample was then tissue dried and an aluminium stub attached to the area with a high strength adhesive.
• Fig 9 depicts a schematic representation of pull-off test equipment in which aluminium stub 1 is attached to test coating 2 with adhesive bond 3.
• the adhesion tests were performed using a commercially available Elcometer Parti 100 test rig with a F20 piston. In testing the stub 1 and top platen 4 are forced apart by the inflation of pneumatic bladder 5. The maximum pneumatic pressure at coating separation was recorded and converted to an adhesion strength using conversion tables supplied with the test rig. In all the samples tested the fracture occurred at the coating - steel interface.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Molecular Biology (AREA)
• Biomedical Technology (AREA)
• Vascular Medicine (AREA)
• Surgery (AREA)
• Dermatology (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Transplantation (AREA)
• Heart & Thoracic Surgery (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pharmacology & Pharmacy (AREA)
• Rheumatology (AREA)
• Pain & Pain Management (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Endocrinology (AREA)
• Reproductive Health (AREA)
• Materials For Medical Uses (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Prostheses (AREA)
• Paints Or Removers (AREA)
• Medicinal Preparation (AREA)

Applications Claiming Priority (3)

Publications (2)

Family

ID=34219617

Family Applications (1)

Country Status (8)

Families Citing this family (23)

Family Cites Families (25)

• 2004
  • 2004-08-18 EP EP04768107A patent/EP1656165B1/fr not_active Expired - Lifetime
  • 2004-08-18 AT AT04768107T patent/ATE417637T1/de not_active IP Right Cessation
  • 2004-08-18 WO PCT/GB2004/003547 patent/WO2005018696A1/fr not_active Ceased
  • 2004-08-18 CA CA002534039A patent/CA2534039A1/fr not_active Abandoned
  • 2004-08-18 AU AU2004266484A patent/AU2004266484B2/en not_active Ceased
  • 2004-08-18 DE DE602004018509T patent/DE602004018509D1/de not_active Expired - Lifetime
  • 2004-08-18 US US10/567,979 patent/US20060286139A1/en not_active Abandoned
  • 2004-08-18 JP JP2006523682A patent/JP4732346B2/ja not_active Expired - Fee Related

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events